Dialkylaminomethylphenyl benzyl alcohols

ABSTRACT

Benzyl alcohols substituted by a diakylaminomethylphenyl moiety in the Alpha -position useful as anti-inflammatories and antidiabetics are obtained by reduction of corresponding benzophenones.

United States Patent Houlihan [5 4] DIALKYLAMINOMETHYLPHENYL BENZYLALCOHOLS [72] Inventor: William J. Houlihan, Mountain Lakes,

[73] Assignee: Sandal-Wander, lnc., Hanover, NJ. [22] Filed: Nov. 17,1969 [2]] Appl. No.: 877,454

Related U.S. Application Data [62] Division of Ser. No. 581,152, Sept.22, 1966, Pat. No.

[52] U.S. Cl. ..260/570, 260/239, 260/247.5,

[51 1 Int. Cl. C07c 87/28 [58] Field of Search 0/570 [56] Reta'encesCited UNITED STATES PATENTS 2,746,969 5/1956 Villanietal ..260/296R [1513,678,111 51 July 18, 1972 OTHER PUBLICATIONS Primary Examiner-AlexMaze] Assistant Examiner-James H. Turnipseed Attorney-Gerald D. Sharkin,Frederick H. Weinfeldt, Robert S. Honor, Walter F. Jewell and Richard E.Vila [57] ABSTRACT Benzyl alcohols substituted by adiakylaminomethylphenyl moiety in the a-position useful asanti-inflammatories and anti-diabetics are obtained by reduction ofcorresponding benzophenones.

2 Claims, No Drawings DIALKYLAMINOMETHYLPHENYL BENZYL ALCOHOLS Thisapplication is a division application of Ser. No. 58l,l52 filed Sept.22, l966now US. Pat. No. 3,497,508, dated Feb. 24, i970.

This invention relates to derivatives of benzyl alcohol. In particular,the invention pertains to a-[(tertiaryaminomethyl) phenyl] benzylalcohols which may be additionally substituted in the a-position with aheterocyclic moiety and methods for preparing the same. The inventionalso relates to intermediates which are useful in preparing the abovecompounds and processes for preparing said intermediates.

The substituted benzyl alcohols of the present invention are of thegeneral formula I OH CHzB

RI! R!!! I wherein each of R and R represents hydrogen; chloro; fluoro;trifluoromethyl; lower alkoxy, preferably containing from one to fourcarbon atoms, e.g., methoxy, ethoxy, propoxy and butoxy; or R and Rtogether form a 3,4-methylenedioxy bridge;

each of R" and R' represents hydrogen; chloro; fluoro; trifluoromethyl;lower alkoxy, preferably containing from one to four carbon atoms, e.g.,methoxy, ethoxy, propoxy and butoxy; or R" and R' together form a 2,3-or 3,4-

methylenedioxy bridge;

R represents hydrogen only;

A represents hydrogen; pyridyl (2-, 3- or 4-), preferably Z-pyridyl; orpiperidyl (2-, 3- or 4), preferably 2 piperidyl; and

B repres nts di-(straight-chain lower alkyl)amino, each of the loweralkyl substituents being the same or different and preferably containingfrom one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl;

or a saturated monocyclic ring containing in the ring, in addition tothe nitrogen atom, from 4 to 6 carbon atoms or 4 to carbon atoms and oneadditional hetero atom of the group nitrogen, oxygen and sulfur, e.g.,morpholino, homomorpholino, pyrrolidino, piperidino, hexahydroazepino,4-phenyl piperazino, 4-lower alkylpiperazino and 4-loweralkylhomopiperazino, the lower alkyl substituents of the last twomentioned groups being straight chain and preferably containing from oneto four carbon atoms.

In structural Formula 1 above and the structural formulas set forthhereinafter, R R' and the substituent CH B may be in any position of thebenzene ring other than that occupied by R except as otherwisespecifically provided herein.

The compounds of Formula I wherein A is pyridyl are prepared by reactingan appropriately substituted benzophenone with a lithium derivative ofpyridine to form the correspondinga-[(tertiaryaminomethyl)phenyll-apyridyl benzyl alcohol. The compoundsof formula I wherein A is piperidyl are readily obtained by reduction ofthe corresponding pyridyl derivative. The over-all process isillustrated by the following reaction scheme:

3 l j QIR O C H: R, L Li H N R' -c- I, Step 1 It R i la

Wherein R, R, R, R", R' and B are as previously defined.

In Step 1 of the process a benzophenone (ll) is reacted with a pyridyllithium compound to form the corresponding pyridyl derivative (la). Thisreaction is carried out in conventional manner employing a suitableinert organic solvent, e.g., diethyl ether, tetrahydrofuran, hexane andheptane, and a reaction temperature of about 20 C. or below. Preferably,the reaction temperature is in the range of from about 20 C. to about 50C. The resulting pyridyl derivative is readily recovered in conventionalmanner. The pyridyl lithium reactant employed in this step is readilyprepared by reacting an appropriate bromopyridine with butyl lithium inconventional manner.

Step 2 of the process involves the formation of the correspondingpiperidyl derivative (lb)via hydrogenation of the pyridyl derivative(la). The hydrogenation is preferably effected catalytically at roomtemperature (20 C.) employing a suitable inert solvent and catalyst,preferably acetic acid and a platinum catalyst (e.g., PtO and a hydrogenpressure of up to about 50 p.s.i.g. The resulting hydrogenated compoundscan be readily recovered in conventional manner.

The compounds of Formula I wherein A is hydrogen are ob- Wherein R, R",R, R", R and B are as previously defined,and Y represents carbonyl (C O)or methylene 2)- The reduction can be effected chemically in a suitableinert organic solvent, e.g., diethyl ether and tetrahydrofuran, and atelevated temperatures, preferably reflux temperature, employing ahydride reducing agent, e.g., sodium borohydride and lithium aluminumhydride. Alternatively, the reduction may be effected catalytically atroom temperature 20 C.) employing a suitable inert solvent, e.g.,ethanol and isopropanol, and an appropriate catalyst, e.g., platinum andnickel. The resulting product (Ic) is readily isolated in conventionalmanner.

The tertiaryaminomethyl substituted benzophenones employed as startingmaterials in the above processes can be prepared by reacting a methylsubstituted benzophenone with a glycol to form the corresponding2-phenyl-2-tolyl-l,3- diox(ol)ane, converting the latter to thecorresponding 2- phenyl-2-(halomethylphenyl)-1,3-diox(ol)ane andtreating the latter with an appropriate amine. This process isparticularly suitable for the preparation of theo-(tertiaryaminomethyl)benzophenones which have heretofore beenextremely difficult to obtain by procedures described in the prior art.Alternatively, the starting benzophenones which contain atertiaryaminomethyl substituent at either the meta or para positions maybe prepared by converting a meta or para-substituted methylbcnzophenoneto the corresponding meta or para-substituted halomethylbenzophenone andtreating the latter with an appropriate amine. These processes may beillustrated structurally as follows:

IIb

wherein R, 'R, R, R", R' and B are as previously defined, X representschloro or bromo and n represents 2 or 3.

The reaction of the benzophenone with the glycol is conveniently carriedout in an inert organic solvent, e.g., benzene, toluene, chlorobenzeneand hexane, and at room temperature or elevated temperatures up toreflux temperature. Preferably, the reaction is carried out at refluxtemperature to facilitate continuous removal of water. To facilitate theformation of water the reaction may be carried out in the presence of acatalytic amount of hydrogen ions such as by the use of a mineral acid,e.g., sulfuric acid, or organic acid, e.g., benzene sulfonic acid andp-toluene-sulfonic acid.

Conversion of the l,3-diox(ol)ane (IV) or benzophenone (Inn) to thecorresponding l,3-diox(ol)ane (V) or halomethylbenzophenone (VI),respectively, is accomplished via halide synthesis employing chlorine,bromine or other positive halogen source, e.g., N-bromosuccinimide, N-chlorophthalimide and N-bromo-N-methylacetamide. The reaction is carriedout at elevated temperatures, preferably reflux temperature, and in asuitable inert organic solvent. When chlorine or bromine is employed,the reaction is desirably carried out in a solvent, such as carbontetrachloride, and in the presence of sunlight or artificial sun source.With the other above-mentioned reagents the reaction is convenientlyeffected in a solvent, such as carbon tetrachloride or chloroform and inthe presence of sunlight or a peroxide initiator, e.g., benzoylperoxide.

The reaction of the l,3-diox(ol)ane (V) or halomethylbenzophenone (V1)with the amine (BH) is readily carried out in conventional manner atroom temperature or below employing a suitable inert organic solvent,e.g., carbon tetrachloride, dichloromethane and hexane, as the reactionmedium.

Various of the methyl substituted benzophenones (Ill) employed above areknown and can be prepared as described in the literature. Such otherswhich may not be specifically known can be prepared from availablematerials in analogous manner.

Various of the benzophenones of formula Ila wherein Y is carbonyl arelikewise known and can be prepared as described in the literature. Suchothers which may not be specifically described in the literature may beprepared from available (CH2)n CH3(O, m, p)

material in similar manner to that described in the literature forpreparing the known compounds.

The compounds of formula I exist in racemic form or in the form ofoptically active isomers. The separation and recovery of the respectiveisomers may be readily accomplished employing conventional techniquesand such isomers are included within the scope of this invention.

The compounds represented by structural formula I are useful becausethey possess pharmacological activity. In particular, the compounds areuseful as anti-inflammatories and antidiabetics. For the above uses thecompounds may be combined with a conventional pharmaceutical carrier,and other adjuvants, if necessary, and administered orally in such formsas tablets, capsules, elixirs, suspensions and solutions or parenterallyin such forms as injectable solutions, suspensions and emulsions.Furthermore, the compounds may be similarly administered in the form oftheir non-toxic, pharmaceutically acceptable acid addition or quaternarysalts. Such salts do not materially differ from the free base in theirpharmacological effects, and are included within the scope of theinvention. Representative of the acid addition salts are the mineralacid salts such as the hydrochloride, hydrobromide, sulfate,

phosphate and the like and the organic acid salts such as the succinate,benzoate, acetate, maleate, p-toluenesulfonate, benzene-sulfonate andthe like. Exemplary of the quaternary salts are those derived fromcommon quaternizing agents such as straight-chain lower alkyl halides,preferably containing from one to four carbon atoms, e.g., methylbromide, ethyl bromide, methyl iodide and ethyl iodide, andstraight-chain di- (lower) alkyl sulfates, e.g., dirnethyl sulfate. Suchsalts are readily prepared from the free base by reacting the base withpharrnacologically-acceptable acids or quatemizing agents inconventional manner.

Furthermore, as noted above, the compounds of formula I exist as opticalisomers. In some cases greater pharmacological activity or otherbeneficial attribute may be found for a particular isomer and in suchinstances administration of such isomer may be preferred.

For the above-mentioned uses, the dosage administered will, or course,vary depending on the compound employed, mode of administration andtreatment intended. However, in general, satisfactory results areobtained when administered at a daily dosage of from about 100milligrams to about 800 milligrams, preferably given in divided dosesthroughout the day or in sustained release form.

A representative formulation of the present invention is a tabletprepared by conventional tabletting techniques containing the followingingredients:

Ingredient Parts by Weight a-[Z-(morpholinomethyl)phenyll-a-(2-piperidyl)benzyl alcohol 40 Tragacanth 2 Lactose 49.5 Corn starch 5Talcum 3 Magnesium stearate 0.5

The compounds of forrnulall in addition to being useful as intermediatesalso possess anti-inflammatory activity and these compounds (intheirfree base fonn or as acid addition or quaternary salts) can beformulated and administered in the same manner as previously indicatedfor compounds of formula l.

The following examples show representative compounds contemplated bythis invention and the manner in which such compounds are prepared.However, it is to be understood that these examples are intended forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention which is defined in theappendedclaims.

Step A. Preparation of Mbtomomethylbenzophenone.

To a flask equipped with a coridenser, stirrer, dropping funnel and gasoutlet tube is added 40g. (0.20 mole) of 4-methylbenzophenone, 22.5 g.(0.257 M1018) of sodium bicarbonate and 250 ml. of carbontetralflbridel'he resulting mixture is stirred and irradiated with anartificial .daylight source (Sun Gun") and then l0.9 ml. (0.22 mole)ofibromine in 90 ml. of carbon tetrachloride is added dropwise. Themixture is refluxed until the color has faded and the refluxingcontinued for an additional two hours thereafter. The resulting mixtureis filtered, and the solvent removed from the filtrate in vacuo on arotary evaporater to obtain 4-bromomethylbenzophenone. Step B.Preparation of 4-morpholinomethylbenzophenone.

To a cooled solution of 31.5 g. of 4-bromomethylbenzophenone in 150 ml.of methylene chloride is added dropwise a solution of 19.9 g. ofmorpholine in ml. of methylene chloride. The mixture is stirredovernight at room temperature, then filtered and the methylene chloridelayer extracted with 2N hydrochloric acid. The acidic extract is thenmade basic by the addition of solid sodium carbonate and then extractedwith chloroform. The chloroform layer is washed with water, dried overmagnesium sulfate and filtered. The filtrate is concentrated on a rotaryevaporater to obtain 4- morpholinomethylbenzophenone. The free base isdissolved in methanol, the resulting solution saturated with hydrogenchloride gas and then treated with anhydrous diethyl ether and thenfiltered to obtain 4-morpholinomethylbenzophenone hydrochloride, m.p.l94l 96 C.

Step C. Preparation of a-[4-( morpholinomethyhphenyl]-a-( 2PYRIDYL)benzyl alcohol.

To a flask equipped with a stirrer, condenser, thermometer, droppingfunnel and gas inlet tube is added, under a nitrogen atmosphere, 260 ml.(0.6 mole) of 15% n-butyllithium in hexane and 140 ml. of anhydrousdiethyl ether. The resulting mixture is cooled in a dry ice-acetone bathto an internal temperature of45 C. and then a solution of 83 g. (0.525mole) or 2- bromopyridine in ml. of diethyl ether is added over a periodof 15 minutes. The resulting mixture is stirred for 10 minutes and thena solution of 42.2 g. (0. l 5 mole) of 4- morpholinomethylbenzophenonein 400 ml. of diethyl ether is added over a 20 minute period. Thecooling bath is then removed and when the internal temperature reachesabout l5 C., a solution of 500 ml. of 2N hydrochloric acid and 250 ml.of water is added dropwise. The aqueous layer is then separated, madebasic with concentrated ammonia and extracted with chloroform. Thechloroform extract is washed with water, dried over magnesium sulfateand evaporated. The residue is chromatographed on a silica gel column toobtain a- [4-( morpholinomethyl)-phenyl ]-2-pyridyl )benzyl alcohol,m.p. l39-l4lC.

A solution of 10 g. of the free base in chloroform is treated withhydrogen chloride gas, and the resulting solids filtered off to obtaina-[4-( morpholinomethyl )phenyl ]-a-( 2- pyridyl)benzyl alcoholmonohydrochloride which decomposes at C.

EXAMPLE 2 a-[ 3-(Morpholinomethyl)phenyl ]-a-( 2-pyridyl )benzyl cohol.

Step A. Preparation of 3-bromomethylbenzophenone.

To a flask equipped with a condenser, stirrer, dropping funnel and gasoutlet tube is added 50 g. (0.26 mole) of 3-methylbenzophenone, 28.3 g.(0.34 mole) of sodium bicarbonate and 310 ml. of carbon tetrachloride.The resulting mixture is stirred and irradiated with an artificialdaylight source (Sun Gun) and then l0.9 (0.22 mole) of bromine in 90 ml.of carbon tetrachloride is added dropwise. The mixture is refluxed untilthe color has faded, and the refluxing continued for an additional 2hours thereafter. The resulting mixture is filtered, and the solventremoved from the filtrate in vacuo on a rotary evaporater to obtain3-bromomethylbenzophenone. Step B. Preparation of3-morpholinomethylbenzophenone.

To a cooled solution of 40 g. of 3-bromomethylbenzophenone in 200 ml. ofmethylene chloride is added dropwise a solution of 25.3 g. of morpholinein 120 ml. of methylene chloride. The mixture is stirred overnight atroom temperature, then filtered and the methylene chloride layerextracted with 2N hydrochloric acid. The acidic extract is then madebasic by the addition of solid sodium carbonate and then extracted withchloroform. The chloroform layer is washed with water, dried overmagnesium sulfate and filtered. The filtrate is concentrated on a rotaryevaporater to obtain 3- morpholinomethylbenzophenone. The free base isdissolved in methanol, the resulting solution saturated with hydrogenchloride gas and then treated with anhydrous diethyl ether and thenfiltered to obtain 3-morpholinomethylbenzophenone hydrochloride, mp. 24l-243 C. (after recrystallization from methanol/diethyl ether).

Step C. Preparation of a-[3-(morpholinomethyl)phenyl]-a-(2PYRlDYL)benzyl alcohol.

To a flask equipped with a stirrer, condenser, thermometer, droppingfunnel and gas inlet tube is added, under a nitrogen atmosphere, 260 ml.(0.6 mole) of 15% n-butyllithium in hexane and 140 ml. of anhydrousdiethyl ether. The resulting mixture is cooled in a dry ice-acetone bathto an internal temperature of 45 C. and then a solution of 83 g. (0.525mole) of 2- bromopyridine in 110 ml. of diethyl ether is added over aperiod of 15 minutes. The resulting mixture is stirred for minutes andthen a solution of 42.2 g. (0.15 mole) of 3-morpholinomethylbenzophenone in 150 ml. of diethyl ether is added over a20 minute period. The cooling bath is then removed and when the internaltemperature reaches about 31 C., a solution of 500 ml. of 2Nhydrochloric acid and 250 ml. of water is added dropwise. The aqueouslayer is then separated, made basic with concentrated ammonia andextracted with chloroform. The chloroform extract is washed with water,dried over magnesium sulfate and evaporated. The residue ischromatographed on a silica gel column to obtain a- [3-(morpholinomethyl)-phenyl]-a-( 2-pyridyl)benzyl alcohol as an oil.

A solution of 15 g. of the free base in diethyl ether is treated withhydrogen chloride gas, and the resulting solids filtered off to obtaina-[ 3-( morpholinomethyl )phenyl]-a-( 2- pyridyl)benzyl alcoholmonohydrochloride which decomposes at 125 C.

EXAMPLE 3 a-[2-( Morpholinomethyl)phenyl]-a-( 2-pyridyl )-pchlorobenzylalcohol.

acid. The mixture is stirred and refluxed for 48 hours, and 'thesolventthen removed on a rotary evaporater to obtain 2-pchlorophenyl-Z-o-tolyll,3-dioxolane as an oil.

Step B. Preparation of 2-p-chlorophenyl-2-(obromomethylphenyl l,3-dioxolane.

To a flask equipped with a condenser, stirrer, dropping funnel and gasoutlet tube is added 27.5 g. of 2-p-chlorophenyl-2-o-tolyl-l,3-dioxolane, l 1.6 g. of sodium bicarbonate and 150 ml. ofcarbon tetrachloride. The resulting mixture is stirred and irradiatedwith an artificial light source (Sun Gun) and then 17.6 g. of bromine in60 ml. of carbon tetrachloride is added dropwise. The mixture isrefluxed until the color has faded, and the refluxing continued for anadditional 2 hours thereafter. The resulting mixture is filtered, andthe solvent removed from the filtrate in vacuo on a rotary evaporater toobtain 2-p-chlorophenyl-2-(o-bromomethyl-phenyl)- l ,3-dioxolane as anoil.

Step C. Preparation chlorobenzophenone.

To a cooled solution of the oily product obtained in Step B in 150 ml.of carbon tetrachloride is added dropwise a solution of 17.4 g. ofmorpholine in 70 m1. of carbon tetrachloride. The mixture is stirredovernight at room temperature, then filtered and the carbontetrachloride layer extracted with 2N hydrochloric acid. The acidicextract is made basic by the addition of solid sodium carbonate and thenextracted with chloroform. The chloroform layer is washed with water,dried over magnesium sulfate and filtered. The filtrate is concentratedon a rotary evaporater, and the residue dissolved in a mixture of 50 ml.of methanol, 5 ml. of water and 10 ml. of concentrated hydrochloricacid. The resulting solution is refluxed for 2 days,and the solvent thenremoved on a rotary evaporater. The residue is made basic with 2N sodiumcarbonate solution and extracted with chloroform. The chloroform extractis dried over sodium of sulfate, filtered and concentrated in vacuo on arotary evaporater to obtain 2- morpholinomethyl-4'-chlorobenzophenone asan oil.

Step D. Preparation of a-[2-( morpholinomethyl)phenyl]-a-( 2PYRlDYL)-p-chlorobenzyl alcohol.

To a flask equipped with a stirrer, condenser, thermometer, droppingfunnel and gas inlet tube is added, under a nitrogen atmosphere, 52 ml.of 15% butyllithium in hexane and ml. of anhydrous diethyl ether. Theresulting mixture is cooled in a dry ice-acetone bath to an internaltemperature of 45 C. and then a solution of 16.6 g. of 2-bromopyridinein 25 ml. of diethyl ether is added over a period of 15 minutes. Theresulting mixture is stirred for 10 minutes, and then a solution of 9.5g. of 2-morpholinomethyl-4'-chlorobenzophenone in ml. of diethyl etheris added over a 20-minute period. The cooling bath is then removed andwhen the internal temperature reaches about 1 5 C., a solution of 100ml. of 2N hydrochloric acid and 50 ml. of water is added dropwise. Theaqueous layer is then separated, made basic with concentrated ammoniaand extracted with chloroform. The chloroform extract is washed withwater, dried over magnesium sulfate and evaporated. The residue ischromatographed on a silica gel column to obtaina-[2-(morpholinomethyl)phenyl]-a-(2- pyridyl)-p-chlorobenzyl alcohol asan oil.

A solution of 2 g. of the free base in chloroform is treated withhydrogen chloride gas, and the resulting solids filtered off to obtaina-[ 2-( morpholinomethyl )phenyl]-a-( Z-pyridyl )-pchlorobenzyl alcoholmonohydrochloride, m.p. l50-l55 C.

of 2-morpholinomethyl-4 EXAMPLE 4 a-[ 3-( Morpholinomethyl )phenyl ]-a-(2-piperidyl )benzyl alcohol.

in @1 N H CHr-N A mixture of 24 g. of a-[3-( morpholinomethyl)phenyl]-60(2-pyridyl)benzyl alcohol, 200 ml. of acetic acid and l g. of platinumdioxide is hydrogenated in a Parr hydrogenation bottle at roomtemperature and 50 p.s.i.g. for 6 hours. The mixture is then filtered,and the filtrate evaporated in vacuo. The residue is made basic withconcentrated ammonia and extracted with chloroform. The chloroformextract is dried over magnesium sulfate, filtered and evaporated. Theoily residue (free base) is dissolved in diethyl ether, and theresulting solution treated with hydrogen chloride gas. The solidmaterial is filtered off to obtain a-[3-(morpho-linomethyl)phenyl]-a 2-(llH 9 10 Q L/ E1 A mixture of 18 g. ofa-[4-morpholinomethyl)phenyl]-a-(2- pyridyl)-benzyl alcohol, 200 ml. ofacetic acid and 0.5 g. of platinum dioxide is hydrogenated in a Parrhydrogenation bottle at room temperature and 50 p.s.i.g. for 12 hours.The mixture is then filtered, and the filtrate evaporated in vacuo. Theresidue is made basic with concentrated ammonia and extracted withchloroform. The chloroform extract is dried over magnesium sulfate,filtered and evaporated. The oily residue (free base) is dissolved indiethyl ether, and the resulting solution treated with hydrogen chloridegas. The solid material is filtered off to obtaina-[4-(morpholinomethyl)phenyl]-a-(2- piperidyl)benzyl alcoholdihydrochloride which decomposes at 203 C.

EXAMPLE 6 a-[2-( Morpholinomethyl)phenyl]-a-( 2-piperidyl)-pchlorobenzylalcohol.

(EH 1 C 0 I N/ A mixture of 5.5 g. of a-[2-(morpholinomethyl)phenyl]-a-(2-pyridyl)-p-chlorobenzyl alcohol, 150 ml. of acetic acid and 0.2 g. ofplatinum dioxide is hydrogenated in a Parr hydrogenation bottle at roomtemperature and 50 p.s.i.g. for 8 hours. The mixture is then filtered,and the filtrate evaporated in vacuo. The residue is made basic withconcentrated ammonia and extracted with chloroform. The chloroformextract is dried over magnesium sulfate, filtered and evaporated. Theoily residue (free base) is dissolved in diethyl ether, and theresulting solution treated with hydrogen chloride gas. The solidmaterial is filtered off to obtain a-[2- (morpholinomethyl)phenyl ]a-(Z-piperidyU-p-chlorobenzyl alcohol dihy-drochloride which decmmposes at200 C.

(5H2 E I To a flask equipped with a stirrer, dropping funnel, condenserand gas inlet is added 8.0 g. (0.21 mole) of lithium aluminum hydrideand 150 ml. of absolute diethyl ether. The system is blanketed withnitrogen and then a solution of 29.5 g. (0.1 mole) ofZ-benzoylbenzomorpholide in 500 ml. of diethyl ether is added dropwisewith stirring. The resulting mixture is refluxed for 7 hours and thencooled in an ice bath. To the cooled mixture is added dropwise 50 ml. ofethyl acetate, 16 ml. of 2N sodium hydroxide and 24 ml. of water. Themixture is then filtered, and the filtrate concentrated on a rotaryevaporater. The residue is crystallized from pentane to obtaina-[Z-(morpholinomethyl)phenyl]benzy1 alcohol, m.p. -90 C.

EXAMPLE 8 Step A. Preparation of 2-phenyl-2-o-to1yl-1,3-dioxolane.

To a flask equipped with a Dean-Stark tube is added 44.4 g. of2-methylbenzophenone, 14.1 g. of ethylene glycol, 250 ml. of benzene and0.5 g. of ptoluenesulfonic acid. The mixture is stirred and refluxed for48 hours, and the solvent then removed on a rotary evaporater. Theresidue is crystallized from benzene-heptane to obtain2-phenyl-2o-tolyll ,3-dioxolane, m.p. 73-75 C.

Step B. Preparation of 2-phenyl-2-(o-bromomethylphenyl)- 1.3-dioxolane.

To a flask equipped with a condenser, stirrer, dropping f unnel and gasoutlet tube is added 45 g. (0.188 mole) of2-phenyl-2-o-to1yl-1,3-dioxolane, 21 g. (0.25 mole) of sodiumbicarbonate and 280 ml. of carbon tetrachloride. The resulting mixtureis stirred and irradiated with an artificial light source (Sun Gun), andthen 10.8 ml. (0.22 mole) of bromine in ml. of

carbon tetrachloride is added dropwise. The mixture isrefluxed until thecolor has faded and the refluxing continued for an additional two hoursthereafter. The resulting mixture is filtered, and the solvent removedfrom the filtrate in vacuo on a rotary evaporater to obtain 2-phenyl-2-(obromomethylphenyl)- 1 ,3-dioxolane.

Step C. Preparation of 2-morpholinomethylbenzophenone.

To a cooled solution of 35.4 g. ofZ-phenyl-Z-(obromomethy1pheny1)-1,3-dioxo1ane in ml. of dichloromethaneis added dropwise a solution of 29.0 g. of morpholine in 150 ml. ofdichloromethane. The mixture is stirred overnight at room temperature,then filtered and the dichloromethane layer extracted with 2Nhydrochloric acid. The acidic extract is made basic by the addition ofsolid sodium carbonate and then extracted with chloroform. Thechloroform layer is washed with water, dried over magnesium sulfate andfiltered. The filtrate is concentrated on a rotary evaporater to obtain2-morpholinomethylbenzophenone. The base is dissolved in methanol, theresulting solution saturated with hydrogen chloride gas and then treatedwith anhydrous diethyl ether and then filtered to obtain2-morpholinomethylbenzophenone hydrochloride, m.p. -182 C. (afterrecrystallization from diethyl ether-ethyl acetate).

Step D. Preparation of a-[2-(morpholinomethyl)pheny1]-a-( 2-PYRIDYL)benzyl alcohol.

Following the procedure of Step C of Example 1 and employing anequivalent amount of 2-morpholinomethylbenzophenone in place of .the4-mor-pholinomethylbenzophenone used therein, there is obtained a-[2-morpho1ino-methyl)phenyl]-oz-( 2-pyridyl)benzy1 alcohol.

EXAMPLE 9 Step A. Preparation of 3-[N-( 3-azabicyclo(3.2.2)nonyl)methyl]benzophenone.

To a cooled solution of 39 g. of 3-bromomethylbenzophenone in 200 ml. ofmethylene chloride is added dropwise a solution of 35.4 g. of3-azabicyclo[3.2.2]nonane in 120 ml. of methylene chloride. The mixtureis stirred overnight at room temperature, then filtered and themethylene chloride layer extracted with 2N hydrochloric acid. The acidicextract is then made basic by the addition of solid sodium carbonate andthen extracted with chloroform. The chlorofonn layer is washed withwater, dried over magnesium sulfate and filtered. The filtrate isconcentrated on a rotary evaporater to obtain3-[N-(3-azabicyclo(3.2.2)nony l)methyl]benzophenone. The free base isdissolved in methanol, the resulting solution saturated with hydrogenchloride gas and then treated with anhydrous diethyl ether and thenfiltered to obtain 3-[N-(3-azabicyclo(3.2.2)nony l)methyl]benzophenonehydrochloride, m.p. l87-190 C. (after recrystallization from ethylacetatediethyl ether).

Step B. Preparation of a-[3-[N-(3-azabicyclo(3.2.2)nonyl)methyl]phenyl]-a-( 2-pyridyl )benzyl alcohol.

Following the procedure of Step C of Example 1 and employing anequivalent amount of 3-[N-(3-azabicyclo(3.2.2)nonyl)methyllbenzophenonein place of the 4- morpholinomethylbenzophenone used therein, there isobtained a-[3-[N-(3-azabicyclo(3.2.2)nonyl)methyl]phenyl]-a-(2-pyridyl)benzyl alcohol.

EXAMPLE l a-[4-[N-( 3-azabicyclo( 3.2.2 )nonyl)methyl]phenyl]-a-( 2-pyridyl)benzyl alcohol.

' tracted with chloroform. The chloroform layer is washed with water,dried over magnesium sulfate and filtered. The filtrate is concentratedon a rotary evaporater to obtain 4-[N-( 3-azab icyclo(3.2.2)nonyl)methyl]benzophenone. The free base is dissolved in methanol, theresulting solution saturated with hydrogen chloride gas and then treatedwith anhydrous diethyl ether and then filtered to obtain4-[N-(3-azabicyclo(3.2.2)nonyl)methyl]benzophenone hydrochloride,

m.p. 253256 C. (after recrystallization from methanolwater).

Step B. Preparation ofa-[4-[N-(3-azabicyclo(3.2.2)nonyl)methyl]phenyl]-a-(2-pyridyl)benzylalcohol.

Following the procedure of Step C of Example 1 and employing anequivalent amount of 4-[N-(3-azabicyclo(3.2.2)nonyl)methyl]benzophenonein place of the 4- morpholinomethylbenzophenone used therein, there isobtained a-[4-[N-( 3-azabicyclo( 3.2.2 )nonyl)methyl]phenyl ]-a-2-pyridyl)benzyl alcohol.

EXAMPLE 1 1 Following the procedure of Example 4 and employing anequivalent amount of the benzyl alcohols enumerated below in place ofthe a-[3 (mor-pholinomethyl)phenyl]-a-(2- pyridyl)benzyl alcohol usedtherein, there are obtained the products set forth below.

Bcnzyl alcohol a-[2-(morpholinomcthyl) phenyl1-a- (2-pyridyl)benzylalcohol.

a-[3-[N(3azabicyclo(3.2.2)nonyl) methyl]phcnyll-a-(2-pyridyl) benzylalcohol.

Product.

a-[Z-(morpholinomethyl)phcnylla-(2-pipvrldyl)benzyl alcohol.

a-[3-[N-(3-azahic ,'clo(3.2.2)nonyl) methyl]phcnyll-a-(2-pipcridyl)benzyl alcohol.

i1-[4-IN-(3-azabicyclo(3.2.2)nonyl) mcthyl]phcnyl]-a-(2-pipcrldyl)benzyl alcohol.

EXAMPLE 12 Following the procedures set forth in Steps A-C of Example 1and employing an equivalent amount of the reactants enumerated below inplace of the corresponding reactants used therein, there are obtainedthe products set forth below. Step A.

4-trlllu0romcthyl-3-broinomcthylbvnzophcnonv. 5-mcthoxy-S-bromomcthyl-STEP B Rcactant Benzophenone Amine Product (a) 5,6-dlchloro-3-hro-Dicthylaminc. 5.64-lichlor0-3-dieth ylmometh ylbenzophenone. amlnomcthylbenzophcnone.

(b) 2,3-dichlor0-4- Piperldinc 2,3-dichloro-4-piperlbromometh ylbenzodlnomcth ylbenzophenone. phcnone.

(c) 5-fluoro-3-bromomethyl- Pyrrolidine5-1luoro-3-pyrrolldlnobenzophenone. moth ylhenzaphcnonc.

(d) 4 -fluor0-4-bromo- 4-mcth ylpip- 4 -fluom l-(N-mcth ylmethylbcnzophenone. crazine. pipcrazinometh yl)- bcnzophenone.

(e) 4trlfluoromethyl-3- Morpholine 4-trifluororneth y1-3- bromomethylbenzomorphollnometh ylphenom. benzophenone.

(i) 5-meth oxy-3-bromo- N-meth yl-N- 5-mcthoxy-3-(N-mcthylrneth ylbenzophenone. eth ylaminc. N-eth ylaminomcth yl)- benzophenone.

(g) 3ethoxy-4-bromo- N-phenyl- 3-cthoxy-4-(N-phenylmethylbenzophenone.plperazine. pipcrazinomethyl)- benzophenone.

(h) 3,4-methylenedloxy- Iiperidinc 3,4 '-meth ylcncdioxy-3-3-bromomethylbenzopiperidlnomethylphenone. bcnzophcnonc.

. STEP C (a) 5.6-dichloro-3-diethyl-2-bromopyria-[ofi-dlchloro-axdlethyl aminomethylbenzodine.amlnomethyhphenyflphenone. a-(Z-pyridyDbenzyl alcohol.

(b) 2,3-dlch1oro-4-piperi- 3-bromopyrla-12-chloro-4-(piperldinodinomethylbenzodine. methyDphenyH-aphenone. (3-pyridyl)-m- (c)5-fiuoro-3-pyrrolidino- 4-bromopyrimethylbenzophenone. dine.

(d) 4-fluoro'4-(Nmethy1- piperazinomethyDbenzophenone.

2-bromopyrldine.

(e) 4-tritluoromethyl-3- 3-bromopyridine.

(h) 3,4-methylenedioxy- B-Diperidlnomethylbenzophenone.

4-bromopyridine.

EXAMPLE 1 3 ehlorobenzyl alcohol. a-[5 fiuoro-3-(pyrrolldiomethyl) pheny1]- a-(4-pyridyl)benzyl alcohol. a-[4-(N-methylpiperazinornethyl) phenyl]-a-(2-pyridyl) p-fluorobenzyl alcohol. a-[3-(mor holinomethyl)phenyl -a-(3-pyridyl)- p-trlfluorometh ylbenzyl alcohol.a-[5-methoxy-3-(N- methyl-N-eth ylaminomethyD- phenyHa-(i -pyridyl)benzyl alcohol. a-[4-N-ph enylpiperazinomethyD-phenyH-a-(3-pyridyl)-m-et.hoxybenzyl alcohol. a-[3-(piperidlnomethyhph enyll-a-(i-pyridyl) 3,4-methylenedioxybenzyl alcohol.

Following the procedure of Example 4 and employing an equivalent amountof the products enumerated in Step C of Example 12 in place of thea-[3-(morpholinomethyl)phenyl]- a-(Z-pyridyDbenzyl alcohol used inExample 4, there are obtained the following compounds.

a. a-[5,6-dichloro-3-(diethylaminomethyl)phenyl]-a-(2- piperidyl)benzylalcohol b a-[ 2-chloro-4-( piperidinomethyl)phenyl ]-a-( 3-piperidyl)benzyl alcohol piperidyl) benzyl alcohol d.

a-[ 5-chloro-3-(pyrrolidinomethyl)phenyl]-a-( 4- a-[ 4-(N-methylpiperazinomethyl )phenyl ]-a-( 2 piperidyU-p-fluorobenzylalcohol e. a-[ 3-( morpholinomethyl)phenyl ]-a-( 3-piperidyl)-ptrifluoro-methylbenzyl alcohol f.a-[S-methoxy-3-(N-methyl-N-ethylaminomethyl)phenyl]-a-(4-piperidyl)benzylalcohol piperidyl )-m-ethoxybenzyl alcohol a-[ 4-(N-phenylpiperazinomethyl)phenyl ]-a-( 3- h. a-[ 3-( piperidinomethyl)phenyl]-a-( 4-piperidyl )-3 ,4-

methylene-dioxybenzyl alcohol EXAMPLE 14 alcohol b) a-[ 2-chloro-4-(piperidinomethyl )phenyll-mchlorobenzyl alcohol c)a-[5-fluoro-3-(pyrrolidinomethyl)phenyl1benzyl alcohol d)a-[4-(N-methylpiperazinomethyl)phenyl1-pfluorobenzyl alcohol e) a-[3-(morpholinomethyl)phenyl]-p-trifluoromethylbenzyl alcohol f)a-[5-methoxy-3-(N methyl-N-ethylaminomethyl)phenyl]benzyl alcohol a-[4N-phenylpiperazinomethyl)phenyll-m-ethoxybenzyl alcohol h)a-[3-(piperidinomethyl)phenyl]-3,4-methylenedioxybenzyl alcohol EXAMPLE15 Following the procedures set forth in Steps A and B of Example 8 andemploying an equivalent amount of the reactants STEP 'A2-Dimethylaminomethylbenzophenone.

Reactants Benzophenone Glycol Product (1) 5,6-dichloro-3-methyl-Ethylene glycol... 2-phenyl-2-(5-6,dichlorobenzophenone.3-methyl)phenyl-1 ,3- Q dioxolane.

(2) 2,3'-dichl0ro-4-meth- Propylene glycol. 2-m-chlorophcnyl2-(2-ylbenzophenone. chloro-4-methyl)phenyl1,3-dioxane. (3)5-fiuoro-3-methyl- Ethylene glycol... 2-phenyl-2-(5-fiuoro-3-benzophenone. methyl)phenyl-1,3-

' dioxolane. (4) 4'-fiuoro-4-methyl- Propylene glycol.Z-p-fluorophenyl-Z-pbenzophenone. tolyl-l,3-dioxane. (5)4'-trifluoromethyl-3- do Z-p-trifluoromethylmethylbenzophenone.phenyl-2-m-tolyl-l ,3-

dioxane. (6) 5-methoxy-3-methyl- Ethylene glycol...2-phonyl-2-(5'methoxybenzophenone. 3-methyl)phcnyl-1,3-

. (lioxolane. 2O (7) 3-ethoxy-4-methyl- Propylene glycoL.2-m-ethoxyphcnyl-2-pbenzophenone. tolyl-1,3-dioxanc. (8)3,4-methylenedioxy- Ethylene glycol... 2-(3,4-mothylencdioxy-3-methylbenzophenonc. phcnyl)2-m-tolyl-l,3-

dioxolane. ('J) 5-chloro-2-mcthylben- Propylene glycoL.2-phcnyl-2-(5-chloro-2- zophenone. mcthyl)phenyl-l,3- 25 dioxano.

(l0 4-methoxy-2-methyl- Ethylene glycol...2-phcnyl-2-(4-rncthoxybenzophenone. 2-methyl)phcnyl-l,3-

dioxolanc.

STEP B Rcactants Halogen Diox(ol)ane source Product (1)2-phenyl-2-(5,6-dichloro-3- Br;2-pheuyl-2-(5,6-dichloromethyl)phenyl-l,3-dioxolanc. S-brQrno-mcthyDphcnyl-l,3-dioxolunc. (2) 2-m-chlorophenyl-2-(2chloro- Cl;2-m-ehlorophenyl-2-(2- 4-methyl )phenyl-1,3-dioxanv.chloro-4-chl0romethyl yl)phcnyl-l,3-di0xanc. (3)2-phenyl-2-(5-fluoro-3-mcth- Cl; 2-phcnyl-2-(5-Iluoro-3- yl) phenyl-l,3'dioxolane. chloromethyl) phenyl- 1,3-dioxolane. (4)2-p-fluoropl1cnyl-2-p-tolyl- B1 2-p-fiuorophenyl-2-p- 1,3-dioxane.bromomethylphenyl- 1,3-dioxane. (5) 2-p-trifluoromethylphenyl-2- llr2-p-trilluoromethyl-2-mm-tolyl-l,3-dioxanc. bromomcthylphenyl-1,3-dioxane. (6) 2-phenyl-2-(5-methoxy-3- llr; 2-phcnyl-2-(5-mcthoxy-3-methyl)phcnyl-1,3-dioxolane. brommethyDphenyl 1,3-di0xolanc. (7)2-m-cthoxyphenyl-2-p-tolyl- Cl: .Z-m-cthoxyphcnyl-Z-p- 1,3-dioxanc.chloromethylphenyl- 1,3-dioxanc. (8) 2-(3,4-methylencdioxyphen- Br;2-(3,4-methyloncdioxy yl)-2-m-tolyl-1,3-doixolano.phcnyl)-2-m-bromomethylphcnyl-l,3- dioxolane. ('J)2-phcnyl-2-(5-ohloro-2-mcth- Cl; 2-phonyl-2-(5-chloro-2-yl)phcnyl-1,3-dioxane. chloromethyDphcnyl- 1,3-dioxane. (l0)2-phenyl-2-(4-methoxy-2- Cl, 2-phenyl-2-( fl W-methyl)phenyl-l,3-dioxolane. chloromcthyl phenyldioxolylanc.

EXAMPLE 16 To a cooled solution of 72.5 g. of2-phenyl-2-(obromomethylphenyl)-l,3-dioxolane in 200 ml. of carbontetrachloride is added dropwise a solution of 20.7 g. of dimethylaminein 200 ml. of carbon tetrachloride. The mixture is stirred overnight atroom temperature, then filtered and the carbon tetrachloride layerextracted with 2N hydrochloric acid. The acidic extract is made basic bythe addition of solid sodium carbonate and then extracted withchloroform. The chloroform layer is washed with water, dried overmagnesium sulfate and filtered. The filtrate is concentrated on a rotaryevaporater to obtain 2-dimethylaminomethylbenzophenone as an oil.

EXAMPLE l7 2-(N-Methylpiperazinomethyl)benzophenone.

To a cooled solution of 72.5 g. of2-phenyl-2-(obromomethylphenyl)-l.3-dioxolane' in 200 ml. of carbontetrachloride is added dropwise a solution of 46 g. of 1-methylpiperazine in 150 ml. of carbon tetrachloride. The mixture isstirred overnight at room temperature, then filtered and the carbontetrachloride layer extracted with 2N hydrochloric acid. The acidicextract is made basic by the addition of solid sodium carbonate and thenextracted with chloroform. The

chloroform layer is washed with water, dried over magnesium sulfate andfiltered. The filtrate is concentrated on a rotary evaporater to obtain2-(N-methylpiperazinomethyl)benzophenone as an oil.

EXAMPLE [8 the carbon tetrachloride layer extracted with 2N hydrochloricacid. The acidic extract is made basic by the addition of solid sodiumcarbonate and then extracted with chloroform. The chloroform layer iswashed with water, dried over magnesium sulfate and filtered. Thefiltrate is concentrated on a rotary evaporater to obtain 2-(N-phenylpiperazinomethyl)benzo henone as an oil.

A solution of 13 g. o the free base in 300 ml. of diethyl ether issaturated with hydrogen chloride gas, the resulting solids filtered offand recrystallized from absolute ethanolmethanol to obtain 2-(N-phenylpiperazinomethyl)benzophenone dihydrochloride, m.p. 229-230 C.

What is claimed is:

l. a-[5,6-dichloro-3-(diethylaminomethyl)phenyllbenzyl alcohol.

2. a-[5-methoxy-3-(N-methyl-N-ethylaminomethyl)phenyl]benzyl alcohol.

2. Alpha -(5-methoxy-3-(N-methyl-N-ethylaminomethyl)phenyl)benzylalcohol.